[go: up one dir, main page]

US7611730B2 - Tramadol-based medicament - Google Patents

Tramadol-based medicament Download PDF

Info

Publication number
US7611730B2
US7611730B2 US10/641,779 US64177903A US7611730B2 US 7611730 B2 US7611730 B2 US 7611730B2 US 64177903 A US64177903 A US 64177903A US 7611730 B2 US7611730 B2 US 7611730B2
Authority
US
United States
Prior art keywords
medicament
release
coating
tramadol
slowing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/641,779
Other languages
English (en)
Other versions
US20040076669A1 (en
Inventor
Johannes Bartholomäus
Elmar Josef Friderichs
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Assigned to GRUNENTHAL GMBH reassignment GRUNENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BARTHOLOMAUS, JOHANNES, FRIDERICHS, ELMAR JOSEF
Publication of US20040076669A1 publication Critical patent/US20040076669A1/en
Application granted granted Critical
Publication of US7611730B2 publication Critical patent/US7611730B2/en
Adjusted expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a medicament containing the racemate of tramadol in slow-release form and the (+)enantiomer of tramadol in immediate-release form.
  • the active pharmaceutical ingredient tramadol is normally employed in the form of its racemate composed of (+)-tramadol—i.e. (1R,2R)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol and ( ⁇ )-tramadol—i.e. (1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol—for controlling moderately severe to severe pain.
  • the analgesic efficacy of tramadol is frequently no longer sufficient for satisfactory therapy of the patient's pain.
  • the analgesic efficacy of tramadol results from a complicated interplay of its enantiomers by a mechanism which comprises a non-opioid in addition to an opioid component of action.
  • the opioid component of action which makes an essential contribution to the analgesic efficacy of tramadol, is attributable to the (+)enantiomer of tramadol and the corresponding metabolite, (+)-O-demethyltramadol.
  • One object of the present invention was therefore to provide a tramadol-based medicament which is also suitable for complete suppression or at least marked alleviation of very severe pain, especially in the initial phase of pain control.
  • This object is achieved according to the invention by providing a medicament which contains the racemate of tramadol in slow-release form and the (+)enantiomer of tramadol in immediate-release form.
  • (+)-tramadol can take place by conventional methods known to the skilled worker, described, for example, in Frankus et al., Arzneim.-Forschung. Drug Res. 28, pages 114-121, 1978 or in EP 0 787715 B1.
  • the corresponding documents are hereby incorporated by reference and are thus regarded as part of the disclosure.
  • the racemate of tramadol is generally available on the market.
  • the medicament of the invention may also contain at least one of the active ingredient components, the racemate or the (+)enantiomer of tramadol, in the form of at least one corresponding physiologically tolerated salt.
  • physiologically tolerated salts are preferably selected from the group of chloride, bromide, sulfate, sulfonate, phosphate, tartrate, teoclate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, diclofenacate, naproxenate, salicylate, acetylsalicylate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate, saccharinate, cyclamate and acesulfamate, particularly preferably from the group of chloride, sulfate, saccharinate, teoclate, embonate, diclofenacate, naproxenate and salicylate.
  • the salt of the respective active ingredient component which is very particularly preferred is the corresponding chloride.
  • physiologically tolerated salts or acid addition salts can be obtained by the conventional methods known to the skilled worker, for example by reacting tramadol racemate or (+)-tramadol with the appropriate acid, preferably in aqueous solution.
  • the medicament of the invention preferably contains from 10 to 75% by weight of (+)-tramadol and from 90 to 25% by weight of slow-release racemic tramadol, particularly preferably from 20 to 50% by weight of (+)-tramadol and from 80 to 50% by weight of the slow-release racemic tramadol, where these amounts are each calculated as active ingredient and not as active ingredient salt and are based on the total amount of active ingredients.
  • the medicament of the invention is suitable preferably for parenteral or oral, particularly preferably for oral, administration.
  • Medicaments which can be administered orally mean in this connection according to the invention those medicaments which are absorbed in the mouth region and those which are taken by mouth but are absorbed only in the gastrointestinal tract.
  • the medicament of the invention is in the form of syrups, transmucosal therapeutic systems, transdermal therapeutic systems, suspensions, tablets, multilayer tablets, coated tablets, capsules, suppositories, easily reconstituted dry preparations or powders.
  • the medicament of the invention is in the form of tablets, multilayer tablets, capsules or as suspension.
  • the slow-release tramadol racemate and the (+)enantiomer of tramadol in the medicament of the invention are each in subunits formulated separately from one another.
  • Subunits for the purposes of the present invention are solid formulations which, besides the respective active ingredient component, may also comprise physiologically tolerated excipients.
  • the subunits of the medicament of the invention are preferably in multiparticulate form.
  • Preferred multiparticulate subunits are microtablets, microcapsules, granules, active ingredient crystals or pellets.
  • the multiparticulate subunits are particularly preferably in the form of microtablets, granules or pellets.
  • the multiparticulate forms can be formulated to give a medicament of the invention by conventional methods known to the skilled worker, for example by packing into capsules or sachets, compression to tablets or by suspending in hydrophilic or lipophilic fluid.
  • the subunits may be different layers of a multilayer tablet, preferably the layers of a bilayer tablet, or the multiparticulate subunits can be compressed to give such layers.
  • the medicament of the invention may comprise the slow-release tramadol racemate formulated in subunits which are provided inter alia with a coating containing (+)-tramadol.
  • the subunits may, where appropriate, also have at least one other coating which does not slow release and is applied directly as protective layer on the surface of the subunits.
  • the multiparticulate subunits are granules or pellets, these preferably have a size in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm. If the multiparticulate subunits are in the form of microtablets, these preferably have a diameter of from 0.5 to 5 mm, particularly preferably 1 to 3 mm and very particularly preferably from 1 to 2 mm.
  • the multiparticulate subunits are active ingredient crystals or microcapsules, these preferably have a diameter of from 10 ⁇ m to 1 mm, particularly preferably from 15 ⁇ m to 0.5 mm.
  • the diameter is very particularly preferably from 30 ⁇ m to 200 ⁇ m.
  • the medicament of the invention may additionally comprise, depending on the embodiment, as further ingredients, the usual physiologically tolerated excipients known to the skilled worker.
  • the medicament of the invention is in the form of tablets or microtablets
  • these may comprise as further physiologically tolerated excipients preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols and/or calcium hydrogen phosphate, and other conventional binders, flow regulators and/or lubricants and, where appropriate, disintegrants known to the skilled worker.
  • the medicament of the invention is in the form of pellets or granules, they may comprise as further physiologically tolerated excipients preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols, calcium hydrogen phosphate, fatty alcohols, esters of glycerol and/or fatty acid esters.
  • a medicament of the invention is in the form of microcapsules, these may comprise, depending on the nature of the method employed to produce them, the conventional physiologically tolerated excipients known to the skilled worker.
  • the medicament of the invention is in the form of a suspension
  • this may, besides the physiologically tolerated suspending medium, comprise other conventional physiologically tolerated excipients known to the skilled worker, such as, for example, pH regulators, regulators to adjust the osmolality, surface-active compounds, viscosity regulators, buffers and/or preservatives.
  • the various formulation forms of the medicament of the invention can be produced by various methods known to the skilled worker.
  • the medicament of the invention is in the form of tablets
  • these can be produced for example by compressing the granules of the enantiomer which have been produced by wet, dry or melt granulation, and the granules of the racemate which have been produced correspondingly and whose release has been slowed in a suitable form, where appropriate with other physiologically tolerated excipients.
  • the tablets can also be produced by compressing multiparticulate, optionally coated, pellets, active ingredient crystals or microcapsules, with slowing of release of the racemic components.
  • the formulations in the form of pellets can preferably be produced by extrusion and spheronization, by agglomerating pelletization or by direct pelletization in a high-speed mixer or in a rotary fluidized bed with simultaneous or subsequent slowing of release of the racemic component.
  • the pellets are particularly preferably produced by extrusion of moist compositions and subsequent spheronization.
  • the enantiomeric component is preferably applied in the form of a coating on the pellets.
  • Microcapsules are produced by conventional microencapsulation methods, such as, for example, by spray drying, spray congealing or coacervation, with a desired slowing of release of the racemic component.
  • the slowing of release of the racemic tramadol is based on a release-slowing coating, on embedding in a release-slowing matrix, on attachment to an ion-exchange resin or a combination of at least two of the aforementioned release-slowing methods.
  • the release-slowing coating is preferably based on a water-insoluble, optionally modified natural or synthetic polymer or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these aforementioned components.
  • Water-insoluble polymers employed for producing a release-slowing coating are preferably poly(meth)acrylates, particularly preferably poly(C 1-4 )-alkyl (meth)acrylates, poly(C 1-4 )dialkylamino-(C 1-4 )-alkyl (meth)acrylates and/or copolymers thereof, very particularly preferably ethyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 2:1, ethyl acrylate/methyl methacrylate/trimethylammoniumethyl methacrylate chloride copolymers with a monomer molar ratio of 1:2:0.1, ethyl acrylate/methyl methacrylate/trimethylammoniumethyl methacrylate chloride copolymers with a monomer molar ratio of 1:2:0.2 or a mixture of at least two of the aforementioned polymers as coating material.
  • coating materials are available on the market as 30% by weight aqueous latex dispersions under the name Eudragit RS30D®, Eudragit NE30D® and Eudragit RL30D®, respectively, and are also preferably employed as such as coating material.
  • polyvinyl acetates where appropriate in combination with further excipients, as water-insoluble polymers for producing the release-slowing coating in the medicament of the invention.
  • polyvinyl acetates are available on the market as aqueous dispersions containing 27% by weight polyvinyl acetate, 2.5% by weight povidon and 0.3% by weight sodium lauryl sulfate (Kollicoat SR 30 D®).
  • the release-slowing coatings of the racemic tramadol are based on water-insoluble cellulose derivatives, preferably alkyl celluloses such as, for example, ethylcellulose, or of cellulose esters such as, for example, cellulose acetate as coating material.
  • the coatings of ethylcellulose or cellulose acetate are preferably applied from aqueous pseudolatex dispersion.
  • Aqueous ethylcellulose pseudolatex dispersions are marketed as 30% by weight dispersions (Aquacoat®) or as 25% by weight dispersions (Surelease®) and are preferably also employed as such as coating material.
  • Natural, semisynthetic or synthetic waxes, fats or fatty alcohols on which the release-slowing coating of the racemic tramadol can be based are preferably carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate (Compritol ATO888®), glycerol ditripalmitostearate (Precirol ATO5®), microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.
  • the coating dispersion or solution may, besides the appropriate polymer, include a conventional, physiologically tolerated plasticizer known to the skilled worker in order to reduce the necessary minimum film-forming temperature.
  • plasticizers are lipophilic diesters of aliphatic or aromatic dicarboxylic acid with C 6 -C 40 and an aliphatic alcohol with C 1 -C 8 , such as, for example, dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic esters of citric acid, such as, for example, triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyalkylene glycols such as, for example, polyethylene glycols or propylene glycols, esters of glycerol such as, for example, triacetin, Myvacet® (acetylated mono- and diglycerides, C 23 H 44 O 5 to C 25 H 47 O 7 ), medium chain-length triglyceride (Miglyol®), with oleic acid or mixtures
  • the release-slowing coating preferably contains the plasticizer(s) in amounts of from 5 to 50% by weight, particularly preferably 10 to 40% by weight and very particularly preferably 10 to 30% by weight, based on the amount of the polymer employed. In individual cases, for example for cellulose acetate, larger amounts of plasticizers may also be employed, preferably up to 110% by weight.
  • the release-slowing coating may include other conventional excipients known to the skilled worker, such as, for example, lubricants, preferably talc or glycerol monostearate, colored pigments, preferably iron oxides or titanium dioxide, or surfactants such as, for example, Tween 80®.
  • lubricants preferably talc or glycerol monostearate
  • colored pigments preferably iron oxides or titanium dioxide
  • surfactants such as, for example, Tween 80®.
  • the profile of release of the slow-release tramadol racemate in the medicament of the invention can be adjusted by conventional methods known to the skilled worker, such as, for example, for the thickness of the coating or for the use of further excipients as ingredients of the coating.
  • suitable excipients are hydrophilic or pH-dependent pore formers such as, for example sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulolse acetate succinate, lactose, polyethylene glycol or mannitol or water-soluble polymers such as, for example, polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the release-slowing coating may also comprise insoluble or lipophilic excipients such as, for example, alkylized silicon dioxide, which is marketed for example as Aerosil R972®, or magnesium stearate, to enhance the slowing of release further.
  • insoluble or lipophilic excipients such as, for example, alkylized silicon dioxide, which is marketed for example as Aerosil R972®, or magnesium stearate, to enhance the slowing of release further.
  • the medicament of the invention itself may also have at least one coating which does not slow release.
  • This may be, for example, a coating to improve the taste or a coating which is resistant to gastric fluid and shows pH-dependent dissolution.
  • the coating which is resistant to gastric fluid allows the corresponding formulation of the medicament of the invention to pass through the gastric tract undissolved, and active ingredient components to be released only in the intestinal tract.
  • the coating which is resistant to gastric fluid preferably dissolves at a pH of between 5 and 7.5.
  • the coating which is resistant to gastric fluid is preferably based on methacrylic acid/methyl methacrylate copolymers with a molar ratio of their respective monomers of 1:1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers with a molar ratio of the respective monomers of 1:2 (Eudragit S®), methacrylic acid/ethyl acrylate copolymers with a molar ratio of the respective monomers of 1:1 (Eudragit L30D-55®) methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a molar ratio of the respective monomers of 7:3:1 (Eudragit FS®), shellac hydroxypropylmethylcellulose acetate succinates, cellulose acetate phthalates or a mixture of at least two of these components, which may also be employed where appropriate in combination with the aforementioned water-insoluble poly(meth)acrylates, preferably in combination with Eudragit NE30D
  • the release-slowing coatings and/or coatings which do not slow release can be applied by conventional methods suitable for the particular coating and known to the skilled worker, such as, for example, by spraying on solutions, dispersions or suspensions, by melting methods or by powder-application methods.
  • the solutions, dispersions or suspensions can be employed in the form of aqueous or organic solutions of dispersions.
  • Aqueous dispersions are preferably employed in this case.
  • Organic solvents which can be used are alcohols, for example ethanol or isopropanol, ketones such as, for example, acetone, esters, for example ethyl acetate, chlorinated hydrocarbons such as, for example, dichloromethane, with alcohols and ketones preferably being employed. It is also possible to employ mixtures of at least two of the aforementioned solvents.
  • the release-slowing coating is preferably applied in such a way that the multiparticulate forms containing the racemic tramadol are coated after their production with the respective release-slowing polymers and, where appropriate, physiologically tolerated excipients from aqueous and/or organic media, preferably from aqueous media, with the aid of the fluidized bed method, and the coating is preferably dried and where appropriate, if necessary, heat-treated at the same time at conventional temperatures in the fluidized bed and/or a coating of (+)-tramadol is applied.
  • the coating is preferably dried at an inlet air temperature in the range from 30 to 50° C., particularly preferably in the range from 35 to 45° C.
  • the drying preferably takes place at a temperature in the range from 50 to 80° C., particularly preferably in the range from 55 to 65° C.
  • Wax coatings can be applied by melt coating in the fluidized bed and, after the coating, be cooled for complete solidification at temperatures below the particular melting range. Wax coatings can also be applied by spraying on solutions thereof in organic solvents.
  • the medicament of the invention may also comprise the racemate of tramadol, preferably uniformly distributed, in a release-slowing matrix.
  • Matrix materials which can be used are physiologically tolerated, hydrophilic materials which are known to the skilled worker.
  • Hydrophilic matrix materials preferably used are polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins.
  • the matrix materials very particularly preferably employed are ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly-(meth)acrylic acid and/or derivatives thereof, such as the salts, amides or esters thereof.
  • Matrix materials composed of hydrophobic materials are likewise preferred, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof.
  • Hydrophobic materials particularly preferably employed are mono- or diglycerides of C 12 -C 30 fatty acids and/or C 12 -C 30 fatty alcohols and/or waxes or mixtures thereof.
  • the tramadol racemate which is present in the release-slowing matrix can be produced by conventional methods known to the skilled worker, and the formulation with (+)-tramadol to give the medicaments of the invention can take place as indicated previously.
  • the total amount of slow-release and immediate-release tramadol active ingredient to be administered to the patient varies for example depending on the patient's weight, on the indication and the severity of the pain or the disorder.
  • the amount to be administered of the slow-release and immediate-release active ingredient, and the release thereof, is preferably adjusted so that administration of the medicament is necessary at most twice, preferably only once, a day and, at the same time, an adequate immediate effect occurs after administration.
  • the medicament of the invention is preferably suitable for controlling pain or for treating urinary incontinence, cough, depression, diarrhea or mental disorders.
  • the medicament of the invention is particularly preferably employed for controlling acute or chronic pain.
  • the medicament of the invention has the advantage that it enables very severe pain to be satisfactorily controlled, while the frequency or the strength of the adverse drug reactions which occur where appropriate with tramadol, such as, for example, nausea, vomiting, sweating, dry mouth, dizziness, convulsions or drowsiness increases only slightly or not at all.
  • (+)-tramadol is available for metabolic activation by the enzyme CYP2D6 to the metabolite (+)—O-demethyltramadol, which has strong analgesic activity, so that the medicament of the invention is particularly suitable also for controlling very severe acute pain.
  • the total dose of tramadol active ingredient to be administered to the patient can be reduced compared with conventional tramadol formulations which, besides slow-release tramadol racemate, also contain an initial dose of racemic tramadol, without the analgesic efficacy of tramadol being reduced thereby.
  • This has the advantage that the adverse drug reactions which occur where appropriate with tramadol occur less often or in attenuated form.
  • a further advantage of the medicament of the invention is that the very low addictive and dependence potential of conventional tramadol formulations is retained, while the contribution of the opioid active component to controlling pain is increased.
  • the particular formulation of the medicament of the invention was tested in the rotating basket apparatus or the paddle stirrer apparatus of Pharm. Eur. at a release medium temperature of 37 ⁇ 0.5° C. at a speed of rotation of 100 revolutions per minute in the case of the rotating basket apparatus and 75 revolutions per minute in the case of the paddle stirrer apparatus in 600 ml of simulated gastric fluid at pH 1.2 without enzymes for 2 hours.
  • the formulation was then tested in 600 ml of simulated intestinal fluid at pH 7.2 without enzymes for a further 8 hours.
  • the amount of (+)-tramadol and ( ⁇ )-tramadol released at each time was determined by HPLC. The values presented are the averages from 6 samples in each case.
  • Pellets containing the racemate of tramadol with an active ingredient content of 55% by weight were produced by aqueous granulation with microcrystalline cellulose and low-substituted hydroxypropylcellulose and subsequent extrusion and spheronization.
  • the pellets obtained in this way were dried, screened to a size of from 800-1 250 ⁇ m and then film-coated in a fluidized bed at an inlet air temperature of 60° C. firstly with 3% by weight hydroxypropylmethylcellulose and talc as coating and subsequently with 11% by weight Surelease® E-7-7050 as release-slowing coating.
  • the film applications are in each case indicated in percent by weight based on the initial weight of the pellets or of the coated pellets.
  • Pellets containing the (+) enantiomer of tramadol with an active ingredient content of 55% by weight were produced by aqueous granulation with microcrystalline cellulose and low-substituted hydroxypropylcellulose and subsequent extrusion and spheronization.
  • the pellets obtained in this way were dried and screened to a size of 800 to 1 250 ⁇ m. These pellets were then coated with a hydroxypropylmethylcellulose (Opadry OY 29020 clear®) coating which did not slow release.
  • Hard gelatin capsules of size 1 were then charged in a suitable two-piece capsule machine with 212 mg of slow-release pellets containing racemic tramadol (equivalent to 100 mg of racemic tramadol hydrochloride) and 47 mg of the immediate-release pellets containing the (+) enantiomer of tramadol (equivalent to 25 mg (+)-tramadol hydrochloride).
  • the release profile was determined in the rotating basket apparatus by the method indicated above and is shown in table 1 below.
  • Pellets containing tramadol racemate and pellets containing the (+) enantiomer of tramadol of the compositions indicated below were produced and coated in analogy to example 1.
  • Hard gelatin capsules of size 0 were then charged in a suitable two-piece capsule machine with 212 mg of the slow-release pellets containing racemic tramadol (equivalent to 100 mg of racemic tramadol hydrochloride) and 94 mg of the immediate-release pellets containing the (+) enantiomer of tramadol (equivalent to 50 mg of (+)-tramadol hydrochloride).
  • the release profile was determined in the rotating basket apparatus by the method indicated above and is shown in table 2 below.
  • Racemic tramadol hydrochloride was homogeneously mixed with microcrystalline cellulose, hydroxypropylmethylcellulose, colloidal silica and magnesium stearate in a cube mixer.
  • (+)-Tramadol chloride was homogeneously mixed with microcrystalline cellulose, colloidal silica and magnesium stearate in a cube mixer. The two mixtures were then compressed in a tablet press (Korsch EK0) eccentric to bilayer tablets with an average diameter of 12 mm. This was done by initially introducing 250 mg of powder mixture of the first layer into the die and precompressing by hand and, after addition of 100 mg of mixture of the second layer, finally compressing the tablets.
  • composition of a bilayer tablet Composition of a bilayer tablet:
  • the release profile was determined in the rotating basket apparatus by the method indicated above and is shown in table 3 below. In a deviation from the indicated method, testing in the simulated intestinal fluid was for 10 hours.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US10/641,779 2001-02-21 2003-08-15 Tramadol-based medicament Expired - Fee Related US7611730B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10108122A DE10108122A1 (de) 2001-02-21 2001-02-21 Arzneimittel auf Basis von Tramadol
DE10108122.7 2001-02-21
PCT/EP2002/001763 WO2002066026A2 (fr) 2001-02-21 2002-02-20 Medicament a base de tramadol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/001763 Continuation WO2002066026A2 (fr) 2001-02-21 2002-02-20 Medicament a base de tramadol

Publications (2)

Publication Number Publication Date
US20040076669A1 US20040076669A1 (en) 2004-04-22
US7611730B2 true US7611730B2 (en) 2009-11-03

Family

ID=7674847

Family Applications (1)

Application Number Title Priority Date Filing Date
US10/641,779 Expired - Fee Related US7611730B2 (en) 2001-02-21 2003-08-15 Tramadol-based medicament

Country Status (15)

Country Link
US (1) US7611730B2 (fr)
EP (1) EP1372624B1 (fr)
JP (1) JP2004521910A (fr)
AT (1) ATE302600T1 (fr)
AU (1) AU2002253039B2 (fr)
CA (1) CA2437242A1 (fr)
DE (2) DE10108122A1 (fr)
DK (1) DK1372624T3 (fr)
ES (1) ES2247320T3 (fr)
HU (1) HUP0303163A3 (fr)
MX (1) MXPA03007467A (fr)
NZ (1) NZ528247A (fr)
PL (1) PL362290A1 (fr)
PT (1) PT1372624E (fr)
WO (1) WO2002066026A2 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070215511A1 (en) * 2006-03-16 2007-09-20 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20130011444A1 (en) * 2011-07-09 2013-01-10 Syntrix Biosystems, Inc. Compositions and methods for overcoming resistance to tramadol
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
US8895622B2 (en) 2011-04-12 2014-11-25 Revogenex Ireland Ltd. Intravenous administration of tramadol
DE102013009114A1 (de) 2013-05-29 2014-12-04 Franz Gerstheimer Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen
US9693949B1 (en) 2015-12-22 2017-07-04 Revogenex Ireland Ltd Intravenous administration of tramadol
US9980900B2 (en) 2015-12-22 2018-05-29 Revogenex Ireland Ltd Intravenous administration of tramadol
US10022321B2 (en) 2016-06-30 2018-07-17 Revogenex Ireland Ltd. Intravenous administration of tramadol
WO2020197576A1 (fr) 2019-03-22 2020-10-01 Syntrix Biosystems Inc. Traitement de la douleur à l'aide de desmétramadol
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US11918689B1 (en) 2020-07-28 2024-03-05 Tris Pharma Inc Liquid clonidine extended release composition
US12458592B1 (en) 2017-09-24 2025-11-04 Tris Pharma, Inc. Extended release amphetamine tablets

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8128957B1 (en) 2002-02-21 2012-03-06 Valeant International (Barbados) Srl Modified release compositions of at least one form of tramadol
US20050182056A9 (en) * 2002-02-21 2005-08-18 Seth Pawan Modified release formulations of at least one form of tramadol
MXPA05000018A (es) * 2002-06-27 2005-04-08 Cilag Ag Formulaciones de pellas esfericas.
UA84277C2 (ru) * 2002-10-25 2008-10-10 Лабофарм Инк. Композиция трамадола с пролонгированным высвобождением с 24-часовым действием
US20050265955A1 (en) * 2004-05-28 2005-12-01 Mallinckrodt Inc. Sustained release preparations
WO2006038339A1 (fr) * 2004-10-01 2006-04-13 Nippon Zoki Pharmaceutical Co., Ltd. Préparation pharmaceutique solide
CN101257894A (zh) 2005-07-07 2008-09-03 法纳姆公司 高水溶性药物的缓释药物组合物
CN101410103B (zh) * 2006-03-30 2013-04-10 日本脏器制药株式会社 固体药物制剂
EP2022778A1 (fr) * 2007-08-07 2009-02-11 Laboratorios del Dr. Esteve S.A. Forme cristalline du sel de (R,R)-tramadol-(S)-naproxène
CZ300468B6 (cs) * 2007-09-20 2009-05-27 Zentiva, A. S Léková forma obsahující tramadol s kontrolovaným uvolnováním po dobu 24 hodin a zpusob její prípravy
GB0811024D0 (en) * 2008-06-17 2008-07-23 E Therapeutics Plc Sustained release treatment of depression
EP2177215A1 (fr) 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de tramadol et NSAID

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0642788A2 (fr) 1993-09-03 1995-03-15 Grünenthal GmbH Médicaments contenant de sel de tramadol avec une libération retardée d'ingrédient actif
DE19601744A1 (de) 1996-01-19 1997-07-31 Gruenenthal Gmbh Verfahren zur Herstellung der Enantiomeren von O-Demethyltramadol
DE19630035A1 (de) 1996-07-25 1998-01-29 Asta Medica Ag Tramadol Multiple Unit Formulierungen
GB2317110A (en) 1996-09-10 1998-03-18 Ninh On Anti-diarrhoeal compositions comprising loperamide
WO1998040053A1 (fr) 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s
WO1999042095A1 (fr) 1998-02-21 1999-08-26 Asta Medica Ag Combinaisons pharmaceutiques contenant du tramadol
EP0787715B1 (fr) 1996-01-19 2000-01-26 Grünenthal GmbH Procédé pour la résolution optique du tramadol
DE9422335U1 (de) 1993-05-10 2000-04-13 Euroceltique S.A., Luxemburg/Luxembourg Formulierung mit kontrollierter Freisetzung
EP1005861A1 (fr) 1997-04-11 2000-06-07 Nippon Shinyaku Co., Ltd. Traitements des mictions frequentes et de l'incontinence urinaire
WO2000032558A1 (fr) 1998-12-02 2000-06-08 Darwin Discovery Limited Produit therapeutique et ses utilisations
DE19927689A1 (de) 1999-06-17 2000-12-21 Gruenenthal Gmbh Orale Darreichungsformen zur Verabreichung einer fixen Kombination von Tramadol und Diclofenac
US6576260B2 (en) * 1999-08-31 2003-06-10 Gruenenthal Gmbh Sustained-release form of administration containing tramadol saccharinate
US6599529B1 (en) * 1997-09-11 2003-07-29 Nycomed Danmark A/S Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)
US20050238715A1 (en) * 2000-10-03 2005-10-27 Penwest Pharmaceuticals Co. Developing a delivery system for multi-pharmaceutical active materials at various release rates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5516803A (en) * 1991-10-30 1996-05-14 Mcneilab, Inc. Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE9422335U1 (de) 1993-05-10 2000-04-13 Euroceltique S.A., Luxemburg/Luxembourg Formulierung mit kontrollierter Freisetzung
EP0642788A2 (fr) 1993-09-03 1995-03-15 Grünenthal GmbH Médicaments contenant de sel de tramadol avec une libération retardée d'ingrédient actif
EP0787715B1 (fr) 1996-01-19 2000-01-26 Grünenthal GmbH Procédé pour la résolution optique du tramadol
DE19601744A1 (de) 1996-01-19 1997-07-31 Gruenenthal Gmbh Verfahren zur Herstellung der Enantiomeren von O-Demethyltramadol
DE19630035A1 (de) 1996-07-25 1998-01-29 Asta Medica Ag Tramadol Multiple Unit Formulierungen
US6436438B1 (en) * 1996-07-25 2002-08-20 Asto-Medica Ag Tramadol multiple unit formulations
GB2317110A (en) 1996-09-10 1998-03-18 Ninh On Anti-diarrhoeal compositions comprising loperamide
WO1998040053A1 (fr) 1997-03-11 1998-09-17 Darwin Discovery Limited Formes galeniques comprenant des parties separees d'enantiomeres r et s
EP1005861A1 (fr) 1997-04-11 2000-06-07 Nippon Shinyaku Co., Ltd. Traitements des mictions frequentes et de l'incontinence urinaire
US6599529B1 (en) * 1997-09-11 2003-07-29 Nycomed Danmark A/S Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)
WO1999042095A1 (fr) 1998-02-21 1999-08-26 Asta Medica Ag Combinaisons pharmaceutiques contenant du tramadol
WO2000032558A1 (fr) 1998-12-02 2000-06-08 Darwin Discovery Limited Produit therapeutique et ses utilisations
DE19927689A1 (de) 1999-06-17 2000-12-21 Gruenenthal Gmbh Orale Darreichungsformen zur Verabreichung einer fixen Kombination von Tramadol und Diclofenac
US6576260B2 (en) * 1999-08-31 2003-06-10 Gruenenthal Gmbh Sustained-release form of administration containing tramadol saccharinate
US20050238715A1 (en) * 2000-10-03 2005-10-27 Penwest Pharmaceuticals Co. Developing a delivery system for multi-pharmaceutical active materials at various release rates

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Analgesic Efficacy And Safety Of Tramadol Enantiomers In Comparison With The Racemate: A Randomised, Double-Blind Study With Gynaecological Patients Using Intravenous Patient-Controlled Analgesia", Ground et al., Pain, Elsevier Science Publishers, vol. 62, No. 3, 1995.
"Complementary And Synergistic Antinociceptive Interaction Between The Enantiomers Of Tramadol", Raffa et al., Journal of Pharmacology and Experimental Therapeutics, 1993, 267(1), 331-40.
"Tramadol Induces Antidepressant-Type Effects In Mice", Rojas-Corrales et al., Life Sciences, vol. 63, No. 12, 1998.
Arzneim.-Forschung. Drug Res. 28, 1978, pp. 114-121.

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8790700B2 (en) 2006-03-16 2014-07-29 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20100166858A1 (en) * 2006-03-16 2010-07-01 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8062667B2 (en) 2006-03-16 2011-11-22 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8202537B2 (en) 2006-03-16 2012-06-19 Tris Pharma Inc Modified release formulations containing drug-ion exchange resin complexes
US8337890B2 (en) 2006-03-16 2012-12-25 Tris Pharma Inc Modified release formulations containing drug-ion exchange resin complexes
US10933143B2 (en) 2006-03-16 2021-03-02 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US8491935B2 (en) 2006-03-16 2013-07-23 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8597684B2 (en) 2006-03-16 2013-12-03 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8747902B2 (en) 2006-03-16 2014-06-10 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9675703B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc Modified release formulations containing drug - ion exchange resin complexes
US20070215511A1 (en) * 2006-03-16 2007-09-20 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8883217B2 (en) 2006-03-16 2014-11-11 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9675704B2 (en) 2006-03-16 2017-06-13 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US10668163B2 (en) 2006-03-16 2020-06-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US9198864B2 (en) 2006-03-16 2015-12-01 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US9522191B2 (en) 2006-03-16 2016-12-20 Tris Pharma, Inc. Modified release formulations containing drug—ion exchange resin complexes
US9549989B2 (en) 2006-03-16 2017-01-24 Tris Pharma, Inc Modified release formulations containing drug-ion exchange resin complexes
US10086087B2 (en) 2006-03-16 2018-10-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US10172958B2 (en) 2006-03-16 2019-01-08 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
US8895622B2 (en) 2011-04-12 2014-11-25 Revogenex Ireland Ltd. Intravenous administration of tramadol
US9566253B2 (en) 2011-04-12 2017-02-14 Revogenex Ireland Ltd. Intravenous administration of tramadol
US9561195B2 (en) 2011-04-12 2017-02-07 Revogenex Ireland Ltd. Intravenous administration of tramadol
US9962343B2 (en) 2011-04-12 2018-05-08 Revogenex Ireland Inc. Intravenous administration of tramadol
US9808432B2 (en) 2011-07-09 2017-11-07 Syntrix Biosystems Inc. Methods for overcoming resistance to tramadol
US9717700B2 (en) 2011-07-09 2017-08-01 Syntrix Biosystems Inc. Methods for overcoming resistance to tramadol
US20130011444A1 (en) * 2011-07-09 2013-01-10 Syntrix Biosystems, Inc. Compositions and methods for overcoming resistance to tramadol
US10702485B2 (en) * 2011-07-09 2020-07-07 Syntrix Biosystems Inc. Compositions and methods for overcoming resistance to tramadol
US9717701B2 (en) 2011-07-09 2017-08-01 Syntrix Biosystems Inc. Compositions for overcoming resistance to tramadol
EP3272339A1 (fr) 2011-07-09 2018-01-24 Syntrix Biosystems, Inc. Compositions et procédés pour surmonter une résistance au tramadol
DE102013009114A1 (de) 2013-05-29 2014-12-04 Franz Gerstheimer Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen
US11590228B1 (en) 2015-09-08 2023-02-28 Tris Pharma, Inc Extended release amphetamine compositions
US9693949B1 (en) 2015-12-22 2017-07-04 Revogenex Ireland Ltd Intravenous administration of tramadol
US10751279B2 (en) 2015-12-22 2020-08-25 Revogenex Ireland Ltd Intravenous administration of tramadol
US10646433B2 (en) 2015-12-22 2020-05-12 Revogenex Ireland Ltd. Intravenous administration of tramadol
US10617635B2 (en) 2015-12-22 2020-04-14 Revogenex Ireland Ltd. Intravenous administration of tramadol
US9968551B2 (en) 2015-12-22 2018-05-15 Revogenex Ireland Ltd Intravenous administration of tramadol
US10729645B2 (en) 2015-12-22 2020-08-04 Revogenex Ireland Ltd. Intravenous administration of tramadol
US10729644B2 (en) 2015-12-22 2020-08-04 Revogenex Ireland Ltd. Intravenous administration of tramadol
US10751278B2 (en) 2015-12-22 2020-08-25 Revogenex Ireland Ltd Intravenous administration of tramadol
US10751277B2 (en) 2015-12-22 2020-08-25 Revogenex Ireland Ltd Intravenous administration of tramadol
US10624842B2 (en) 2015-12-22 2020-04-21 Revogenex Ireland Ltd. Intravenous administration of tramadol
US9980900B2 (en) 2015-12-22 2018-05-29 Revogenex Ireland Ltd Intravenous administration of tramadol
US10022321B2 (en) 2016-06-30 2018-07-17 Revogenex Ireland Ltd. Intravenous administration of tramadol
US11590081B1 (en) 2017-09-24 2023-02-28 Tris Pharma, Inc Extended release amphetamine tablets
US12076441B2 (en) 2017-09-24 2024-09-03 Tris Pharma, Inc. Extended release amphetamine tablets
US12458592B1 (en) 2017-09-24 2025-11-04 Tris Pharma, Inc. Extended release amphetamine tablets
WO2020197576A1 (fr) 2019-03-22 2020-10-01 Syntrix Biosystems Inc. Traitement de la douleur à l'aide de desmétramadol
US11918689B1 (en) 2020-07-28 2024-03-05 Tris Pharma Inc Liquid clonidine extended release composition

Also Published As

Publication number Publication date
NZ528247A (en) 2005-02-25
EP1372624B1 (fr) 2005-08-24
HUP0303163A3 (en) 2008-03-28
ES2247320T3 (es) 2006-03-01
CA2437242A1 (fr) 2002-08-29
AU2002253039B2 (en) 2005-12-22
DE10108122A1 (de) 2002-10-02
DK1372624T3 (da) 2005-11-14
US20040076669A1 (en) 2004-04-22
PT1372624E (pt) 2005-11-30
DE50204027D1 (de) 2005-09-29
MXPA03007467A (es) 2003-12-04
HUP0303163A2 (hu) 2003-12-29
EP1372624A2 (fr) 2004-01-02
ATE302600T1 (de) 2005-09-15
PL362290A1 (en) 2004-10-18
WO2002066026A3 (fr) 2002-11-07
JP2004521910A (ja) 2004-07-22
WO2002066026A2 (fr) 2002-08-29

Similar Documents

Publication Publication Date Title
US7611730B2 (en) Tramadol-based medicament
US6576260B2 (en) Sustained-release form of administration containing tramadol saccharinate
US5411745A (en) Powder-layered morphine sulfate formulations
CA2348090C (fr) Systeme d'administration de medicaments par doses pulsees par voie orale
AU781707B2 (en) Oral pharmaceutical forms of administration with a delayed action
US6077533A (en) Powder-layered oral dosage forms
JPH11171775A (ja) テオフィリン徐放性錠剤
HUP0201687A2 (en) Oral administration form for administering a fixed tramadol and diclofenac combination
TW201740932A (zh) 美沙拉 的口服醫藥組成物
US11622938B2 (en) Oral pharmaceutical compositions of nicotinamide
JP2665858B2 (ja) 持効性塩酸オキシブチニン製剤
WO2009024858A1 (fr) Forme posologique à libération contrôlée de galantamine
RU2727721C2 (ru) Фармацевтическая композиция с замедленным высвобождением, содержащая ривастигмин
US8173164B2 (en) Oral administration forms for administering a fixed tramadol and diclofenac combination
ZA200608190B (en) Controleld release dosage for GABA receptor antagonist
RU2292877C2 (ru) Лекарственная ретард-форма, содержащая сахаринат трамадола
US20140112995A1 (en) Multi-layered, multiple unit pharmaceutical compositions
CA2874677A1 (fr) Compositions pharmaceutiques a unites multiples multicouches
MXPA99002404A (en) Controlled release dosage form of [r-(z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2. 2]oct-3-yl)acetonitrile monohydrochloride

Legal Events

Date Code Title Description
AS Assignment

Owner name: GRUNENTHAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BARTHOLOMAUS, JOHANNES;FRIDERICHS, ELMAR JOSEF;REEL/FRAME:014401/0251

Effective date: 20030508

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20211103